Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis

Catherine Y. Cheng; Nuria M. Gutierrez; Mardiana B. Marzuki; Xiaohua Lu; Taylor W. Foreman; Bhairav Paleja; Bernett Lee; Akhila Balachander; Jinmiao Chen; Liana Tsenova; Natalia Kurepina; Karen W.W. Teng; Kim West; Smriti Mehra; Francesca Zolezzi; Michael Poidinger; Barry Kreiswirth; Deepak Kaushal; Hardy Kornfeld; Evan W. Newell; Amit Singhal

doi:10.1126/sciimmunol.aaj1789

Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis

Catherine Y. Cheng, Nuria M. Gutierrez, Mardiana B. Marzuki, Xiaohua Lu, Taylor W. Foreman, Bhairav Paleja, Bernett Lee, Akhila Balachander, Jinmiao Chen, Liana Tsenova, Natalia Kurepina, Karen W.W. Teng, Kim West, Smriti Mehra, Francesca Zolezzi, Michael Poidinger, Barry Kreiswirth, Deepak Kaushal, Hardy Kornfeld, Evan W. NewellAmit Singhal

Hackensack Meridian School of Medicine, Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

Mycobacterium tuberculosis (Mtb) executes a plethora of immune-evasive mechanisms, which contribute to its pathogenesis, limited efficacy of current therapy, and the emergence of drug-resistant strains. This has led to resurgence in attempts to develop new therapeutic strategies/targets against tuberculosis (TB). We show that Mtb down-regulates sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)–dependent deacetylase, in monocytes/macrophages, TB animal models, and TB patients with active disease. Activation of SIRT1 reduced intracellular growth of drug-susceptible and drug-resistant strains of Mtb and induced phagosome-lysosome fusion and autophagy in a SIRT1-dependent manner. SIRT1 activation dampened Mtb-mediated persistent inflammatory responses via deacetylation of RelA/p65, leading to impaired binding of RelA/p65 on the promoter of inflammatory genes. In Mtb-infected mice, the use of SIRT1 activators ameliorated lung pathology, reduced chronic inflammation, and enhanced efficacy of anti-TB drug. Mass cytometry–based high-dimensional analysis revealed that SIRT1 activation mediated modulation of lung myeloid cells in Mtb-infected mice. Myeloid cell–specific SIRT1 knockout mice display increased inflammatory responses and susceptibility to Mtb infection. Collectively, these results provide a link between SIRT1 activation and TB pathogenesis and indicate a potential of SIRT1 activators in designing an effective and clinically relevant host-directed therapies for TB.

Original language	English
Article number	eaaj1789
Journal	Science immunology
Volume	2
Issue number	9
DOIs	https://doi.org/10.1126/sciimmunol.aaj1789
State	Published - 2017

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cheng, C. Y., Gutierrez, N. M., Marzuki, M. B., Lu, X., Foreman, T. W., Paleja, B., Lee, B., Balachander, A., Chen, J., Tsenova, L., Kurepina, N., Teng, K. W. W., West, K., Mehra, S., Zolezzi, F., Poidinger, M., Kreiswirth, B., Kaushal, D., Kornfeld, H., ... Singhal, A. (2017). Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis. Science immunology, 2(9), Article eaaj1789. https://doi.org/10.1126/sciimmunol.aaj1789

@article{1fa58972d13b4b1fa22bd3cd2daa15f0,

title = "Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis",

abstract = "Mycobacterium tuberculosis (Mtb) executes a plethora of immune-evasive mechanisms, which contribute to its pathogenesis, limited efficacy of current therapy, and the emergence of drug-resistant strains. This has led to resurgence in attempts to develop new therapeutic strategies/targets against tuberculosis (TB). We show that Mtb down-regulates sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase, in monocytes/macrophages, TB animal models, and TB patients with active disease. Activation of SIRT1 reduced intracellular growth of drug-susceptible and drug-resistant strains of Mtb and induced phagosome-lysosome fusion and autophagy in a SIRT1-dependent manner. SIRT1 activation dampened Mtb-mediated persistent inflammatory responses via deacetylation of RelA/p65, leading to impaired binding of RelA/p65 on the promoter of inflammatory genes. In Mtb-infected mice, the use of SIRT1 activators ameliorated lung pathology, reduced chronic inflammation, and enhanced efficacy of anti-TB drug. Mass cytometry–based high-dimensional analysis revealed that SIRT1 activation mediated modulation of lung myeloid cells in Mtb-infected mice. Myeloid cell–specific SIRT1 knockout mice display increased inflammatory responses and susceptibility to Mtb infection. Collectively, these results provide a link between SIRT1 activation and TB pathogenesis and indicate a potential of SIRT1 activators in designing an effective and clinically relevant host-directed therapies for TB.",

author = "Cheng, {Catherine Y.} and Gutierrez, {Nuria M.} and Marzuki, {Mardiana B.} and Xiaohua Lu and Foreman, {Taylor W.} and Bhairav Paleja and Bernett Lee and Akhila Balachander and Jinmiao Chen and Liana Tsenova and Natalia Kurepina and Teng, {Karen W.W.} and Kim West and Smriti Mehra and Francesca Zolezzi and Michael Poidinger and Barry Kreiswirth and Deepak Kaushal and Hardy Kornfeld and Newell, {Evan W.} and Amit Singhal",

note = "Publisher Copyright: 2017 {\textcopyright} The Authors,",

year = "2017",

doi = "10.1126/sciimmunol.aaj1789",

language = "English",

volume = "2",

journal = "Science immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

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Cheng, CY, Gutierrez, NM, Marzuki, MB, Lu, X, Foreman, TW, Paleja, B, Lee, B, Balachander, A, Chen, J, Tsenova, L, Kurepina, N, Teng, KWW, West, K, Mehra, S, Zolezzi, F, Poidinger, M, Kreiswirth, B, Kaushal, D, Kornfeld, H, Newell, EW & Singhal, A 2017, 'Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis', Science immunology, vol. 2, no. 9, eaaj1789. https://doi.org/10.1126/sciimmunol.aaj1789

TY - JOUR

T1 - Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis

AU - Cheng, Catherine Y.

AU - Gutierrez, Nuria M.

AU - Marzuki, Mardiana B.

AU - Lu, Xiaohua

AU - Foreman, Taylor W.

AU - Paleja, Bhairav

AU - Lee, Bernett

AU - Balachander, Akhila

AU - Chen, Jinmiao

AU - Tsenova, Liana

AU - Kurepina, Natalia

AU - Teng, Karen W.W.

AU - West, Kim

AU - Mehra, Smriti

AU - Zolezzi, Francesca

AU - Poidinger, Michael

AU - Kreiswirth, Barry

AU - Kaushal, Deepak

AU - Kornfeld, Hardy

AU - Newell, Evan W.

AU - Singhal, Amit

PY - 2017

Y1 - 2017

N2 - Mycobacterium tuberculosis (Mtb) executes a plethora of immune-evasive mechanisms, which contribute to its pathogenesis, limited efficacy of current therapy, and the emergence of drug-resistant strains. This has led to resurgence in attempts to develop new therapeutic strategies/targets against tuberculosis (TB). We show that Mtb down-regulates sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase, in monocytes/macrophages, TB animal models, and TB patients with active disease. Activation of SIRT1 reduced intracellular growth of drug-susceptible and drug-resistant strains of Mtb and induced phagosome-lysosome fusion and autophagy in a SIRT1-dependent manner. SIRT1 activation dampened Mtb-mediated persistent inflammatory responses via deacetylation of RelA/p65, leading to impaired binding of RelA/p65 on the promoter of inflammatory genes. In Mtb-infected mice, the use of SIRT1 activators ameliorated lung pathology, reduced chronic inflammation, and enhanced efficacy of anti-TB drug. Mass cytometry–based high-dimensional analysis revealed that SIRT1 activation mediated modulation of lung myeloid cells in Mtb-infected mice. Myeloid cell–specific SIRT1 knockout mice display increased inflammatory responses and susceptibility to Mtb infection. Collectively, these results provide a link between SIRT1 activation and TB pathogenesis and indicate a potential of SIRT1 activators in designing an effective and clinically relevant host-directed therapies for TB.

AB - Mycobacterium tuberculosis (Mtb) executes a plethora of immune-evasive mechanisms, which contribute to its pathogenesis, limited efficacy of current therapy, and the emergence of drug-resistant strains. This has led to resurgence in attempts to develop new therapeutic strategies/targets against tuberculosis (TB). We show that Mtb down-regulates sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase, in monocytes/macrophages, TB animal models, and TB patients with active disease. Activation of SIRT1 reduced intracellular growth of drug-susceptible and drug-resistant strains of Mtb and induced phagosome-lysosome fusion and autophagy in a SIRT1-dependent manner. SIRT1 activation dampened Mtb-mediated persistent inflammatory responses via deacetylation of RelA/p65, leading to impaired binding of RelA/p65 on the promoter of inflammatory genes. In Mtb-infected mice, the use of SIRT1 activators ameliorated lung pathology, reduced chronic inflammation, and enhanced efficacy of anti-TB drug. Mass cytometry–based high-dimensional analysis revealed that SIRT1 activation mediated modulation of lung myeloid cells in Mtb-infected mice. Myeloid cell–specific SIRT1 knockout mice display increased inflammatory responses and susceptibility to Mtb infection. Collectively, these results provide a link between SIRT1 activation and TB pathogenesis and indicate a potential of SIRT1 activators in designing an effective and clinically relevant host-directed therapies for TB.

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U2 - 10.1126/sciimmunol.aaj1789

DO - 10.1126/sciimmunol.aaj1789

M3 - Article

C2 - 28707004

SN - 2470-9468

VL - 2

JO - Science immunology

JF - Science immunology

IS - 9

M1 - eaaj1789

ER -

Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis

Abstract

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